The present invention relates to a series of new derivatives of the compounds known as "milbemycins", particularly of miblemycin A.sub.3, milbemycin A.sub.4, milbemycin D and of the corresponding compound having a sec-butyl group at the 25-position.
The milbemycins are a series of macrolide compounds known to have anthelmintic, acaricidal and insecticidal activities. Milbemycin D was disclosed in U.S. Pat. No. 4,346,171, where it was referred to as "compound B-41D", and milbemycins A.sub.3 and A.sub.4 were disclosed in U.S. Pat. No. 3,950,360. These compounds may be represented by the formula (A): ##STR1## in which R.sup.1 represents a methyl group, an ethyl group or an isopropyl group, these compounds being milbemycin A.sub.3, milbemycin A.sub.4 and milbemycin D, respectively. For the avoidance of doubt, formula (A) also shows the numbering applied to the positions most relevant to the compounds of the present invention.
These milbemycin compounds may be isolated from cultures of the Streptomyces strain B-41-146, which has been deposited at the Fermentation Research Institute, Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan, whence it is available under the accession number FERM-1438. The compounds have been found to have valuable anthelmintic and acaricidal activities.
Subsequently, other derivatives of the milbemycins, primarily by substitution at the 5-position and/or the 13-position, have been discovered, and some of these have shown potentially valuable anthelmintic and/or acaricidal and/or insecticidal activities. For example, U.S. Pat. No. 4,093,629 discloses certain 13-bromo derivatives, and 13-halo derivatives more generally are disclosed in U.S. Pat. No. 4,173,571. Closer to the present invention are the 5-ketomilbemycin derivatives [i.e. similar to formula (A) but the hydroxy group and the hydrogen atom at the 5-position are replaced by an oxygen, .dbd.O, atom] disclosed in U.S. Pat. No. 4,423,209 and their 5-oxime derivatives [i.e. formula (A) but the hydroxy group and hydrogen atom at the 5-position are replaced by a group of formula .dbd.N--OH], as disclosed in U.S. Pat. No. 4,547,520; however, unlike the compounds of the invention but like their parent milbemycins, most of these compounds are unsubstituted at the 13-position; only the compounds of U.S. Pat. No. 4,423,209 have a 13-hydroxy substituent.
A 13-halomilbemycin derivative is disclosed in Tetrahedron Letters, 24 (48), 5333-5336, but no biological activity is disclosed for the compound.
We have now discovered a series of 13-halo derivatives of the 5-ketomilbemycins and their oximes which have demonstrated, in certain test systems, activities, particularly acaricidal activities, far better than the corresponding activities of their parent compounds.